This application is a 371 of pct/81593/11332 filed Jul. 21, 1993.
The present invention is directed toward pyrimidine-cyanoguanidine compounds which are potassium channel blockers useful in the treatment of cardiovascular disorders such as congestive heart failure and hypertension. The pyrimidine-cyanoguanidine compounds of this invention, unlike other cyanoguanidines, block potassium channel conduction in vascular smooth muscle and ATP-sensitive potassium channels in apical membranes of Kidney.
It is known that K.sup.+ channels are important for regulating potassium excretion by the kidney and it has been proposed that inhibition of ATP-sensitive K.sup.+ channel conduction in apical cell membranes of the thick ascending limb of Henle's loop would reduce potassium recycling across the membrane and thus reduce sodium resorption via the Na.sup.+ -2Cl.sup.- -K.sup.+ co-transporter. It has also been proposed that inhibition of the ATP-sensitive K.sup.+ channels of apical membranes in principal cells of the initial and cortical collecting tubule would reduce K.sup.+ secretion, the primary source of urinary potassium. K.sup.+ channel antagonist activities necessary to produce the observed eukalemic natriuresis have been documented in the rat kidney.
The subject compounds are effective blockers for the ATP-sensitive potassium channels of the thick ascending limb of Henle's loop and the principal cells of the initial and cortical collecting tubules of the kidney. This activity results in an enhanced urinary excretion of sodium and water without enhanced potassium excretion. This provides a useful diuresis which is not complicated by an undesirable reduction in plasma potassium levels or hypokalemia.
Thus, the subject series of cyanoguanidines, although very closely related to the K.sup.+ channel agonist pinacidil and related compounds, are potent K.sup.+ channel antagonists.